Pharmaceutical combinations comprising insulin and at least an agent selected from meloxicam, bromfenac sodium, acetylsalicylic acid, salicyclic acid and paracetamol

ABSTRACT

The present invention relates to pharmaceutical insulin compositions comprising insulin, a preservative, and at least one selected from the group consisting of aspirin, acetaminophen, dexamethasone, heparin, meloxicam, bromfenac sodium, salicylic acid; and the use of the compositions to treat diabetes.

The present invention provides an insulin composition comprisinginsulin, preservative, and at least one agent selected from the groupconsisting of meloxicam, bromfenac sodium, acetylsalicylic acid,salicylic acid, paracetamol, heparin, and dexamethasone. The presentinsulin composition can extend the wear-time of a continuoussubcutaneous insulin infusion (CSII) therapy device, by maintainingefficacy and stability.

Commercially available insulin infusion sets for CSII are currentlyindicated for 2-3 days use. Use of CSII at a single site is limited dueto impaired infusion site efficacy after approximately 3 to 5 days. Aninfusion set that lasts greater than 3 days, and preferably 7 to 14days, and in some embodiments, up to 21 days, is desired for patientconvenience, consistent efficacy, to reduce waste, and to ultimatelyenable a once-weekly or once-biweekly change-over time frame.

Certain methods and systems for inhibiting foreign body responses indiabetic patients and to decrease infusion site loss are disclosed in WO2015/061493 (Medtronic). Despite these efforts, there is a need foradditional means to extend the efficiency of single site CSII forpatients with diabetes.

The insulin composition of this invention is suited for use with a pumpand an infusion set and offers patients desired enhanced usage time at asingle site for CSII.

The present invention provides a composition comprising insulin,preservative, and at least one agent selected from the group consistingof meloxicam, bromfenac sodium, acetylsalicylic acid, paracetamol,salicylic acid, heparin, and dexamethasone.

In an embodiment the composition comprises insulin, preservative, and atleast one agent selected from the group consisting of sodium,acetylsalicylic acid, paracetamol, and salicylic acid. In an embodimentis a composition comprising insulin, preservative, and at least oneagent selected from the group consisting of meloxicam, bromfenac sodium,and dexamethasone.

In an embodiment the preservative is m-cresol. In certain embodimentsthe preservative is phenol. In certain embodiments, the preservative isphenol and m-cresol.

In addition, the present invention also provides a method of treatingdiabetes comprising administering to a human in need thereof aneffective dose of a pharmaceutical composition comprising insulin,preservative, and at least one agent selected from the group consistingof meloxicam, bromfenac sodium, acetylsalicylic acid, paracetamol,salicylic acid, heparin, and dexamethasone.

In addition, the present invention provides a pharmaceutical compositionfor use in therapy. More particularly, the present invention provides apharmaceutical composition for use in the treatment of diabetes. Thepresent invention also provides the use of a pharmaceutical compositionin the manufacture of a medicament for the treatment of diabetes whereinthe pharmaceutical composition comprises insulin, preservative, and atleast one agent selected from the group consisting of meloxicam,bromfenac sodium, acetylsalicylic acid, paracetamol, salicylic acid,heparin, and dexamethasone.

In addition, the present invention provides an article of manufacturecomprising a pharmaceutical composition comprising insulin,preservative, and at least one agent selected from the group consistingof meloxicam, bromfenac sodium, acetylsalicylic acid, paracetamol,salicylic acid, heparin, and dexamethasone.

More particularly, in certain aspects, the article of manufacture is amulti-use vial, a cartridge, a re-usable pen injector, a pump device forcontinuous subcutaneous insulin infusion therapy, and an article for usein a pump device for continuous subcutaneous insulin infusion therapy.

In an embodiment, this invention provides a pharmaceutical compositioncomprising:

-   -   a. insulin;    -   b. zinc, in a total concentration from about 0.2 mM to about 4        mM;    -   c. a preservative;    -   d. a buffer; and

at least one agent selected from the group consisting of meloxicam,bromfenac sodium, acetylsalicylic acid, salicylic acid, and paracetamol.

In an embodiment, this invention provides a pharmaceutical compositioncomprising:

-   -   a. insulin;    -   b. zinc, in a total concentration from about 0.2 to about 4 mM;    -   c. a preservative;    -   d. a buffer; and

at least one agent selected from the group consisting of acetylsalicylicacid, salicylic acid, and paracetamol.

In an embodiment, a buffer is for example, at least one selected fromthe group consisting of citrate, phosphate and TRIS.

In an embodiment, the insulin component in the composition is an ultrarapid-acting insulin. In a further embodiment, the composition comprisesm-cresol.

In an embodiment, this invention provides a pharmaceutical compositioncomprising: a rapid-acting insulin; zinc, in a concentration from about0.2 mM to about 4 mM; a preservative; and

at least one agent selected from the group consisting of meloxicam,bromfenac sodium, acetylsalicylic acid, salicylic acid, and paracetamol.

In an embodiment, this invention provides a pharmaceutical compositioncomprising: a rapid-acting insulin; zinc, in a concentration from about0.2 mM to about 4 mM; a preservative; and

at least one agent selected from the group consisting of meloxicam,bromfenac sodium, acetylsalicylic acid, salicylic acid, heparin,paracetamol, and dexmethasone.

In certain embodiments, the compositions of the present invention haveconcentrations of the insulin from about 40 to about 1000 IU/mL. Incertain embodiments, the composition of the present invention haveconcentrations of the insulin from about 100 to about 500 IU/mL. Incertain embodiments, the compositions of the present invention haveconcentrations of the insulin from about 100 to about 300 IU/mL. Incertain preferred embodiments, the compositions comprise an insulinconcentration of about 100 IU/mL or about 200 IU/mL.

When used herein, the term “composition” refers to a combination ofinsulin and the other ingredients or excipients wherein the insulin andother ingredients or excipients are in a single combined formulation,typically an aqueous formulation.

As used herein, the term “about” means within plus or minus 10 percent.The term may preferably mean within plus or minus 5 percent. In certainembodiments, the term may preferably mean within plus or minus 2percent.

“Insulin” as used herein means human insulin or an insulin analog.Insulin analogs are well-known and include for example, but are notlimited to, insulin lispro (commercially available as HUMALOG®), insulinaspart (commercially available as NOVOLOG®), insulin glulisine(commercially available as APIDRA®). In one preferred embodiment,insulin is insulin lispro. In one preferred embodiment, insulin isultra-rapid-acting insulin. In one preferred embodiment, the insulin isa rapid-acting insulin.

As used herein, “rapid-acting insulin” means an insulin that actsquickly to minimize the rise in blood sugar that typically followseating. For example, this type of insulin typically begins to work inabout 15 minutes after injection or dosage, peaks in about one hour, andcontinues to work for about 2 to 4 hours after dosage. The skilledartisan readily recognizes that rapid-acting insulins include, forexample, insulin lispro and other commercially available insulins.

As used herein, “ultra-rapid-acting insulin” means an insulin thatbegins to work about 25% to about 50% faster than a “rapid-acting”insulin. For example, an ultra-rapid insulin may begin to work withinabout 5 to about 10 minutes after dosage. The artisan will recognizethat ultra-rapid-acting insulins may include for example, FIASP® andother ultra-rapid-acting insulin formulations.

Meloxicam, bromfenac sodium, acetylsalicylic acid, paracetamol,salicylic acid, heparin, and dexamethasone are well-known agents. Asused herein, “meloxicam” means IUPAC:4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide1,1-dioxide. As used herein, “bromfenac sodium” means IUPAC: Sodium2-[2-amino-3-(4-bromobenzoyl)phenyl]acetate.

As used herein, “acetylsalicylic acid” means IUPAC: 2-acetoxybenzoicacid, also known as aspirin or acetylsalicylate. As used herein“paracetamol” means IUPAC: N-(4-hydroxyphenyl)acetamide, also known as4-acetamidophenol or acetaminophen. “Salicylic acid” as used hereinmeans IUPAC: 2-hydroxybenzoic acid, a known hydrolysis product ofaspirin. As used herein “heparin” means IUPAC Name:(2R,3R,4R,5S,6S)-6-[(2R,3R,4R,5R,6S)-6-[(2S,3 S,4S,5R,6R)-6-[(2S,3S,4R,5R,6R)-5-acetamido-4,6-dihydroxy-2-(sulfooxymethyl)oxan-3-yl]oxy-2-carboxy-4-hydroxy-5-sulfooxyoxan-3-yl]oxy-2-(hydroxymethyl)-5-(sulfoamino)-4-sulfooxyoxan-3-yl]oxy-3,4-dihydroxy-5-sulfooxyoxane-2-carboxylicacid, also known as heparin sodium and heparin sulfate. As used herein“dexamethasone” means IUPAC Name:(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one,also known as dexamethasone sodium phosphate. In one preferredembodiment, the composition includes paracetamol. In an embodiment thecomposition includes acetylsalicylic acid. In an embodiment, thecomposition includes heparin. In an embodiment, the composition includesdexamethasone. In an embodiment, the composition includes dexamethasoneand salicylic acid. In an embodiment the agent is at least one selectedfrom the group consisting of aspirin and heparin. In an embodiment theagent is at least one selected from the group consisting of salicylicacid and paracetamol. In an embodiment the agent is at least oneselected from the group consisting of salicylic acid and acetylsalicylicacid. In an embodiment the agent is at least one selected from the groupconsisting of salicylic acid and heparin. In an embodiment thecomposition includes meloxicam. In an embodiment the compositionincludes bromfenac sodium. In an embodiment, the agent is at least oneselected from the group consisting of acetylsalicylic acid, meloxicam,and bromfenac sodium.

In an embodiment, acetylsalicylic is present in an amount of from about780 mg/mL to about 16,000 mg/mL. In an embodiment, acetylsalicylic acidis present in an amount of from about 0.18 mg/mL to about 1600 mg/mL. Inan embodiment, acetylsalicylic acid is present at a concentration ofabout 10 mM. In an embodiment, acetylsalicylic acid is present at aconcentration of about 20 mM.

In an embodiment, paracetamol is present an amount of from about 0.4mg/mL to about 900 mg/mL. In an embodiment, paracetamol is present at aconcentration of about 30 mM. In an embodiment, paracetamol is presentat a concentration of about 60 mM.

In an embodiment, dexamethasone is present in an amount of from about0.004 mg/mL to about 5.75 mg/mL. In an embodiment, dexamethasone ispresent in an amount of from about 1 mg/mL to about 5 mg/mL.

In an embodiment the heparin is present in an amount of from about 1.2U/mL to 1200 U/mL. In an embodiment, the heparin is present in an amountof from about 1.2 U/mL to about 267 U/mL. In certain embodiments, theheparin concentration is less than 267 U/mL heparin.

In an embodiment, the salicylic acid concentration is from about 780mg/mL to about 16,000 mg/mL. In an embodiment, the salicylic acidconcentration is from about 0.18 mg/mL to about 1600 mg/mL. In anembodiment, the salicylic acid concentration is about 10 mM. In anembodiment, salicylic acid is present at a concentration of about 20 mM.

In an embodiment, the meloxicam concentration is from about 0.015 mg/mLto about 5.0 mg/mL. In an embodiment, meloxicam is present at aconcentration of about 0.025 mg/mL to about 2.0 mg/mL. In an embodiment,meloxicam is present at a concentration of about 0.025 mg/mL to about0.50 mg/mL. In an embodiment meloxicam is present at a concentration ofabout 1.5 mg/mL to about 3.0 mg/mL.

In an embodiment, the bromfenac concentration is from about 0.1 mg/mL toabout 7.0 mg/mL. In an embodiment, bromfenac is present at aconcentration of about 0.2 mg/mL to about 3.0 mg/mL. In an embodiment,bromfenac is present at a concentration of about 0.17 mg/mL to about 1.0mg/mL. In an embodiment, bromfenac is present at a concentration ofabout 0.5 mg/mL to about 3.0 mg/mL.

Surfactants disclosed for use in parenteral pharmaceutical compositionsinclude polysorbates, such as polysorbate 20 (TWEEN® 20) and polysorbate80 (Tween® 80), polyethylene glycols such as PEG 400, PEG 3000, TRITON™X-100, polyethylene glycols such as polyoxyethylene (23) lauryl ether(CAS Number: 9002-92-0, sold under trade name BRIJ®), alkoxylated fattyacids, such as MYRJ′, polypropylene glycols, block copolymers such aspoloxamer 188 (CAS Number 9003-11-6, sold under trade name PLURONIC®F-68) and poloxamer 407 (PLURONIC® F127), sorbitan alkyl esters (e.g.,SPAN®), maltosides, polyethoxylated castor oil (e.g., KOLLIPHOR®,CREMOPHOR®) and trehalose and derivatives thereof, such as trehaloselaurate ester. In certain embodiments, the surfactant is selected fromthe group consisting of polyoxyethylene (23) lauryl ether, poloxamer 188trehalose laurate ester, polysorbate 20 and polysorbate 80. In anembodiment, the surfactant is poloxamer 188. In an embodiment, thesurfactant is polysorbate 20. In an embodiment, the surfactant ispolysorbate 80. In certain embodiments, the concentration of surfactantranges from about 0.003 to about 2% w/v, about 0.003 to about 0.3% w/vor about 0.01 to about 0.2% w/v. In certain embodiments, theconcentration of surfactant ranges from about 0.003 to about 2% w/v,about 0.003 to about 0.3% w/v or about 0.01 to about 0.2% w/v. Incertain embodiments wherein the surfactant is poloxamer 188, theconcentration of poloxamer 188 ranges from about 0.06 to about 0.12 w/v.In certain embodiments, the concentration of polysorbate 20 is about0.06% w/v. In certain embodiments, poloxamer 188 is about 0.06% w/v. Inother embodiments, the concentration of polysorbate 20 is about 0.09%w/v. In other embodiments, the concentration of polysorbate 20 is about0.12% w/v. In other embodiments, the concentration of poloxamer 188 isabout 0.12% w/v.

Use of CSII at a single site for 2 to 3 days is associated with woundformation from application of the infusion set and associated tissueremodeling, a defining factor in the efficacy of parenteral drugdelivery systems and can vary from patient-to-patient. Wound formationand stimulation of fibrous encapsulation structures follows a complexseries of inter-related biochemical pathways, which likely havegenome-derived variations.

Beyond the wound and foreign body responses, additional considerationsrelate to patient sensitivity towards drugs like insulin and theexcipients their formulations contain. There is a need for an insulincomposition to facilitate use of CSII at a single site for more than 3days for patients.

Dexamethasone is a corticosteroid, anti-inflammatory, andimmunosuppressive. Glucocorticoids and the glucocorticoid receptorreside at the apex of a regulatory network that blocks inflammatory andimmune pathways. The anti-inflammatory effects of glucocorticoids arelargely due to a reduction in the synthesis and/or release of a varietyof inflammatory mediators, including the prostaglandins that are alsoinhibited by non-steroidal anti-inflammatory drugs (“NSAIDS”).Glucocorticoids are shown to inhibit certain aspects of leukocytefunction, which is associated with their immunosuppressant effect.Glucocorticoids inhibit phagocytosis among macrophages and reduce thenumber and activity of specific subsets of T lymphocytes. Compared toNSAIDS, glucocorticoids exhibit superior anti-inflammatory efficacy. Dueto their somewhat delayed action, their effect on an initial catheterprovisional matrix material may show differences compared to thosemedicines effecting hematostasis. Other glucocorticoid agents, such asbetamethasone, are contemplated for use in an insulin composition ofthis invention. Other NSAIDS contemplated for use in an insulincomposition of this invention include ibuprofen (about 12.8 mg/mL toabout 1600 mg/mL), indomethacin (about 0.06 mg/mL to about 70 mg/mL),and salsalate (about 12 mg/mL to about 6000 mg/mL).

Heparin is an inhibitor of thrombin, binding to the enzyme inhibitorantithrombin III (“AT”), causing a conformational change that isassociated with its activation. The activated AT is believed toinactivate thrombin, factor Xa, and other proteases reducing bloodcoagulation. The anticoagulation effects of heparin administration mayreduce inflammatory signaling from the wound site. It is envisioned thatheparin may interact with other inflammatory cytokines and proteins,further reducing the site fibrous matrix. Other agents envisioned hereinthat similarly inhibit the blood clotting cascade and may be useful inan insulin composition as claimed herein include abciximab (about 0.07mg/mL to about 200 mg/mL), aggrastat (about 0.01 mg/mL to about 33.6mg/mL), argatroban (about 0.77 mg/mL to about 768 mg/mL), eptifibitide(about 0.5 mg/mL to about 428 mg/mL), desirudin (about 0.12 mg/mL toabout 120 mg/mL), dipyridamole (about 1.2 mg/mL to about 800 mg/mL),lepirudin (about 1.1 mg/mL to about 1120 mg/mL), and nafamostat (about0.01 mg/mL to about 5.4 mg/mL).

As used herein “preservative” is selected from m-cresol, phenol, andmixtures thereof. In a preferred embodiment, the preservative ism-cresol. In certain embodiments, the concentration of m-cresol is fromabout 2.5 to about 3.8 mg/mL. In certain embodiments, the concentrationof m-cresol is about 3.15 mg/mL. In certain embodiments, the phenolconcentration is about 8.5 mg/mL. In certain embodiments, thepreservative is a mixture of phenol and m-cresol. In certainembodiments, the preservative is a mixture of phenol at a concentrationof about 1.5 mg/mL and m-cresol at a concentration of about 1.72 mg/mL.

As noted above, the present invention also provides an article ofmanufacture comprising a pharmaceutical composition. In certainembodiments, the article of manufacture is a multi-use vial. In otherembodiments, the article of manufacture is a multi-use pre-filledcartridge. In other embodiments, the article of manufacture is a pumpdevice for continuous subcutaneous insulin infusion therapy. In otherembodiments, the article of manufacture is a container closure systemfor use in a pump device for continuous subcutaneous insulin infusiontherapy

In certain embodiments, the insulin concentration is from about 40 U/mLto about 1000 U/mL. In certain embodiments the insulin concentration isfrom about 100 U/mL to about 1000 U/mL.

In certain embodiments, the composition is stable to allow for use in apump device for continuous subcutaneous insulin infusion therapy for upto 7 days. In certain embodiments, the composition is stable to allowfor use in a pump device for CSII for up to 21 days.

The present invention is delivered locally to the site of CSII. Asillustrated by the Examples, the formulation is placed in the insulinpump cartridge comprises insulin, a preservative, and the agent,However, the present invention envisions delivery of the agent locallyto the infusion site. For example the agent may be provided by directdissolution within the fluid path itself. Accordingly, any method thatwill deliver the agent in sufficient quantities and with a sufficientelution profile are envisioned. For example, the agents shown belowillustrate this drug delivery profile:

Amount Amount Concentration Delivered Delivered Drug in Solution per dayper week Meloxicam 0.015-0.050 mg/mL 0.010-0.027 mg 0.091-0.182 mgBromfenac sodium 0.187-0.746 mg/mL 0.101-0.403 mg 0.707-2.820 mgDexamethasone 3.6 mg/mL 6 mg 42 mg Salicylic Acid 0.02 mmol/mL 10.8 mmol75.6 mmol

The abbreviations used herein are defined according to AldrichimicaActa, Vol. 17, No. 1, 1984. Other abbreviations as used herein aredefined as follows: “CSII” means continuous subcutaneous insulininfusion, “HPLC” refers to high performance liquid chromatography, “PBS”means phosphate-buffered saline, “HMWP” means high molecular weightpolymer.

EXAMPLES Example 1 Acetylsalicylic Acid and Acetaminophen Preparation ofFormulation Stocks:

Acetylsalicylic acid stock (30 mM) is prepared by adding 74.9 mg ofsolid to 13.9 mL of water. The acetylsalicylic acid stock solution issolubilized by the addition of a small aliquot (<50 uL) of 5 M NaOH toincrease the pH to 12.5. Paracetamol stock (90 mM) is prepared by adding101.7 mg of solid paracetamol to 7.5 mL of water (pH=5.3). The phosphatebuffer stock (700 mM) is prepared by adding 1.5 g of Na₂HPO₄-7H₂O to 8.1mL of water (pH 9.0). The m-cresol stock solution (226.6 mM) is preparedby adding 49 mg of m-cresol to 2 mL of PBS. The zinc stock (30 mM) isprepared by adding 50.2 mg of zinc oxide (ZnO) to 20.6 mL of 75 mM HCl.

Insulin Co-Formulation Preparation:

Insulin lispro control formulation (750 uL) is prepared with a finalconcentration of 0.6 mM insulin lispro (3.5 mg/mL; 137.7 uL of 3267 uMZn²⁺ free stock), 29.13 mM m-cresol (3.15 mg/mL; 96.4 uL stock), 7 mMNa₂HPO₄-7H₂O (7.5 uL of stock, pH 9.0), and 0.3 mM ZnO (7.5 uL of stock;3 mol Zn²⁺/hexamer). The insulin lispro/acetylsalicylic acidformulations are prepared as the control formulation above with asupplementation of 10 mM or 20 mM acetylsalicylic acid as finalconcentrations (250 uL and 500 uL of stock, respectively). Additionally,insulin lispro/paracetamol formulations are prepared as the controlformulation above with a supplementation of 30 mM or 60 mM paracetamolas final concentrations (250 uL and 500 uL of stock, respectively). Twoseparate formulations are prepared as described above with 20 mMacetylsalicylic acid or 90 mM paracetamol; however, the m-cresol isexcluded from the formulation. All samples are adjusted with water toachieve the final concentrations. The pH is adjusted to 7.4+/−0.1 withdilute HCl and/or NaOH. All samples are filtered using 0.22 um syringefilter (Millex-GV; REF SLGV013SL). An aliquot of 300 uL of eachformulation described above, as well as an aliquot of 300 uL ofcommercial Humalog®, are placed into separate 2-mL screw-cap glass vialsand incubated static at 37° C. The insulin lispro main peak loss andhigh molecular weight polymer (HMWP) growth over time are tracked usinganalytical reversed-phase HPLC for 24 days. The samples are visiblyinspected for particulate or precipitation throughout study.

Analytical RP-HPLC Conditions:

Insulin lispro main peak loss and HMWP growth are tracked over timeusing HPLC. Mobile phase buffer A (100 mM sodium sulfate+10%acetonitrile, pH to 2.3) and mobile phase buffer B (80% acetonitrile inwater) are filtered through 0.22 um filter. The gradient is presented inTable 1. The UV detector is set to 214 nm wavelength, column temperatureto 40° C., flowrate to 1 mL/min, and injection volume to 5 uL of eachformulation. Main peak and HMWP are reported as an area percent frommain peak region at approximately 10 mins retention time and HMWP regionbetween 17 and 29 mins. The data is collected and slope analysis of rateof change per day is performed using Y by X plots using commercialsoftware.

TABLE 1 Analytical RP-HPLC assay for determination of insulin main peakloss and polymer formation. Time (min) Buffer A (%) Buffer B (%) 0.0076.8 23.2 3.00 74.5 25.5 15.00 74.5 25.5 21.00 72.4 27.6 26.00 51.8 48.227.00 51.8 48.2 27.10 76.8 23.2 35.00 76.8 23.2

TABLE 2 Tabulated rates of change (%/day) for main peak loss and HMWPgrowth over time as determined by analytical RP-HPLC. Change in MainPeak Change in HMWP Sample (%/Day) (%/Day) 10 mM Aspirin −0.12 +/− 0.050.03 +/− 0.01 20 mM Aspirin −0.17 +/− 0.11 0.09 +/− 0.07 20 mMAcetylsalicylic −1.47 +/− 0.26 0.84 +/− 0.17 acid/No m-cresol 30 mMParacetamol −0.33 +/− 0.22 0.14 +/− 0.03 60 mM Paracetamol −0.37 +/−0.01 0.27 +/− 0.05 60 mM Paracetamol/No −0.94 +/− 0.03 0.50 +/− 0.02m-cresol Insulin lispro control −0.16 +/− 0.05  0.04 +/− 0.003Commercial Humalog −0.18 +/− 0.04 0.04 +/− 0.01

The tabulated data (Table 2) summarizes the rates of change (%/day) inmain peak and HMWP growth for insulin lispro co-formulated with eitheracetylsalicylic acid or paracetamol, in the absence and presence ofm-cresol. For comparison, commercial Humalog® and laboratory preparedinsulin lispro control, based on the Humalog® formulation, are presentedas controls. The inclusion of acetylsalicylic acid or paracetamol hasminimal impact on insulin lispro stability. The absence of m-cresolresults in a higher rate of insulin main peak loss and polymer formationcompared to m-cresol containing formulations.

Example 2 Heparin

Insulin with heparin formulations are prepared by adding 0.3 mL ofheparin sodium (10,000 U/mL in water) and 0.58 mL of 0.9% sodiumchloride to 10 mL of U110 insulin lispro to provide a final formulationcomprising 276 U/mL heparin sodium, 101 U/mL insulin lispro, 16.22 mg/mLglycerin, 3.19 mg/mL m-cresol, 1.91 mg/mL sodium phosphate dibasicheptahydrate, 0.46 mg/mL sodium chloride, and 0.02 mg/mL Zn²⁺. Theinsulin/heparin solution is transferred to pump cartridges for use inthe pre-clinical in vivo model.

Pre-Clinical In Vivo Model:

A preclinical model using non-diabetic, castrated male Yucatan mini pigsin non-terminal, randomized, cross-over fashion is useful for mimickingthe behavior of insulin pharmacokinetics and glucose pharmacodynamics inhuman subjects over the course of continuous infusion at a singleinfusion site for up to 10 days. In this model, one infusion set isplaced on the abdomen of each animal, and each site receives the samevolume of insulin placebo (formulations identical to U100 Humalog® butcontaining no active pharmaceutical ingredient) for 3× daily bolusinfusion of 0.1 mL, and continuous basal infusion of 0.01 mL/h. Testgroups with non-insulin medicaments receive placebo with the medicamentadded at the desired concentration. On days 0, 3, 5, 7, and 10 followinginfusion set placement, after an overnight fast, each animal is given aninfusion bolus of U100 Humalog (with or without a non-insulinmedicament) in accordance with their body weight (0.15 U/kg). Glucoseand insulin concentrations are then assessed via serial blood samplescollected from each animal at the following time points relative to thetime of insulin bolus delivery: −30, −20, 0, (deliver insulin bolus),15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 300, and 360 min. Atconclusion of blood sampling on day 10, infusion sets are carefullyremoved and assessed for catheter damage. The site of infusion is alsoassessed for signed of infection, irritation, erythema, and edema. Thismodel can demonstrate significant reductions in plasma insulinconcentrations and consequent glucose lowering over time indicative ofthe loss of infusion site efficacy. The pre-clinical model is used toshow the effects of compositions claimed herein.

The data in Table 3 represents the insulin pharmacokinetic data for U100Humalog and the insulin/heparin co-formulation, respectively, and overthe course of 10 days of continuous infusion at a single infusion site.The diminishing concentration of serum insulin over time for the ControlGroup of Table 3 is typical for CSII, while the maintenance of insulinpharmacokinetics without any loss in signal for 7 consecutive days forthe insulin/heparin co-formulation Test Group in Table 3 supports thedesired result.

TABLE 3 Maximum changes in plasma glucose concentration after dosingwith 0.15 U/kg of U100 insulin lispro or 0.15 U/kg of U100 insulinlispro spiked with 267 U/mL heparin sodium, on days 0, 3, 5, 7, and 10of continuous infusion at a single infusion site. Variation is standarderror of the mean. P-values derived via a 2-sample T-test. MaximumChange in Plasma Glucose Days of (Mean ± SEM) Continuous Control GroupHeparin-Treated P-value Infusion (N = 6) (N = 7) (α = 0.05) 0 −71.8 ±5.2 −66.9 ± 2.6 0.416 3 −57.0 ± 6.0 −65.1 ± 2.7 0.261 5 −42.2 ± 8.0−62.0 ± 2.8 0.057 7  −36.2 ± 10.3 −62.9 ± 5.3 0.055 10  −39.1 ± 10.4−22.3 ± 8.7 0.247

The effect on insulin efficacy is further demonstrated by evaluating themaximum serum insulin concentrations over time. This study showed thatthe glucose lowering effect of an insulin bolus is sustained for 7 daysin heparin-treated animals, but steadily declines from day 0 in animalsnot treated with heparin. N=6 for each group.

Example 3 Dexamethasone

This study can be used to evaluate the beneficial effect of localdelivery of dexamethasone during SCII. In this experiment, dexamethasoneis not co-formulated with insulin; rather, the 0.25 mg/h infusion isachieved using a commercially available solution of 10 mg/mLdexamethasone delivered using an infusion pump programmed for a basaldelivery of 25 uL/h. On days 0, 3, 5, 7, and 10 following infusion setplacement, the animals are fasted followed by dosing with 0.15 U/kginsulin lispro using an infusion pump. During the time between insulindoses, the animals receive 25 uL/h continuous infusion of either 10mg/mL dexamethasone or insulin placebo.

Results using the methods set forth support that local delivery ofdexamethosone via co-formulation with insulin is a preferred route ofadministration to achieve the desired result. Results from the studysupport that the concentration of 0.25 mg/h (6 mg/d) is effective inimproving infusion site viability for 5 days.

Dexamethasone insulin formulations are prepared substantially asfollows: 1.1 mL of a 100 mg/mL dexamethasone solution in sodiumphosphate buffer is added to 10 mL U110 insulin lispro. The formulationis prepared using standard techniques to provide a formulationcomprising 10 mg/mL dexamethasone, 99 U/mL insulin lispro, 15.84 mg/mLglycerin, 3.12 mg/mL m-cresol, 2.07 mg/mL sodium phosphate, and 0.02mg/mL Zn²⁺.

Results shown in Table 4 indicate that dexamethasone can improveinfusion site viability for up to 5 days, whereas orally delivereddexamethasone has no effect.

TABLE 4 Baseline-adjusted areas under the curve for plasma glucose overthe 6 hours following an insulin bolus of 0.15 U/kg of U100 insulinlispro, on days 0, 3, 5, 7, and 10 of continuous infusion of 0.25 mg/hdexamethasone (Subcutaneous Dexamethasone), 25 uL/h insulin placebo(Control Group), and 25 uL/h insulin placebo + twice daily oraladministration of 3 mg dexamethasone (Oral Dexamethasone). Variation isstandard error of the mean. P-values derived via a 2-sample T-testbetween the Subcutaneous Dexamethasone and Control Group data sets.Plasma Glucose Days of Control Subcutaneous Oral * P-value vs.Continuous Group Dexamethasone Dexamethasone Control Infusion (N = 5) (N= 5)* (N = 5) (α = 0.05) 0 −15110 ± 2482  −16700 ± 2027 −14218 ± 754 0.635 3 −7015 ± 2418 −12591 ± 873  −5265 ± 2130 0.082 5 −8266 ± 1422−12297 ± 755  −8109 ± 987  0.046 7 −5517 ± 1340  −7149 ± 1555 −7750 ±1491 0.453 10 −4440 ± 1242 −4893 ± 775 −4266 ± 1551 0.767

Example 4 Meloxicam and Bromfenac Sodium Preparation of FormulationStocks:

Humalog U200 stock solution is prepared by dissolving 7.55 g of insulinlispro powder in approximately 788 g of mixture containing 3.15 g ofm-cresol, 16 g of glycerin in water, supplemented with 1.96 mL of 12.44mg/mL of zinc oxide stock solution. After adding insulin lispro powder,the pH of the solution is reduced to pH 3.0+/−0.2 by adding suitableamount of 10% w/w HCl and stirring until complete dissolution isobserved or up to a maximum of 2 hours. Following insulin lisprodissolution, the pH of the solution is increased to pH 7.6+/−0.1 byadding suitable amount of 10% w/w NaOH, allowing the mixture tore-dissolve the solids for 30 minutes and then adjusting the pH down topH 7.3+/−0.1. Then, 90 mL of Tris base prepared at 55.55 mM and pH7.2-pH 7.4 in water is added to this solution After this, the solutionpH is adjusted down to pH 7.25+/−0.5 by adding suitable volume of 10%w/w HCl. The solution is supplemented with additional water until itsweight equals 915 g. The final solution is mixed for another 5 minutesand then filtered through a 0.22 um PVDF filter into a clean container.

Meloxicam stock (3.0 mg/mL) is prepared by adding 179.8 mg of solidfirst to 20 mL of water, then increasing the pH to above pH 12.0 using10% w/w NaOH, followed by addition of more water until 59.8 mL of totalwater volume has been added. This stock solution is mixed for at least30 minutes or until complete dissolution is observed.

Humalog U200-Meloxicam Co-Formulation Preparation:

The Humalog U220 stock solution is taken in clean glass beakers with astir bars. Suitable volume of the meloxicam (3 mg/mL) stock solution isadded along with suitable volume of water to equal 0.01, 0.05, 0.18, or0.27 mg/mL meloxicam and mixed well. The pH of the solution is adjustedat pH 7.25+/−0.05 by adding suitable volume of 10% w/w HCl. Eachsolution is filtered through 0.22 um PVDF filters and then filled intoclean glass vials. The vials are kept at 30° C. for 36 days.

Humalog U200-Bromfenac Sodium Co-Formulation Preparation:

The Humalog U220 stock solution is diluted with water to equal toU200/mL insulin lispro concentration. Suitable quantity of BromfenacSodium powder is weighed out in separate clean glass beakers with atarget volume of 200-220 mL of solution containing 0.075, 0.187 and0.746 mg/mL bromfenac sodium respectively. Based on the weighedquantity, the appropriate volume of Humalog U200 prepared earlier isadded and mixed for 5 minutes to fully dissolve the bromfenac sodium.The resulting solution filtered through 0.22 um PVDF filters and thenfilled into clean glass vials. The vials are kept at 30° C. for 36 days.

Analytical SEC Conditions for Humalog U200—Meloxicam CoformulationSamples:

The mobile phase is prepared by mixing a 1.0 mg/mL stock solution ofL-arginine with acetonitrile and glacial acetic acid in the ratio65:20:15 respectively. The mobile phase is flowed at 0.5 mL/min througha size-exclusion HPLC column maintained at ambient temperature(WAT201549, 30 cm×7.8 mm, Waters). 50 uL of each coformulation sample isinjected and monitored for a run time of 40 minutes at 276 nm using aUV-Visible detector. Main peak and high molecular weight polymer (HMWP)are reported as an area percent from main peak region at approximately18 mins retention time and HMWP region between 10 and 17 mins. The datais collected at different points during the 36-day incubation period at30° C. Using slope analysis, the rate of change of HMWP per day isperformed using Y by X plots using commercial software.

Analytical SEC Conditions for Humalog U200—Bromfenac SodiumCoformulation Samples:

The mobile phase is prepared by mixing acetonitrile and water in 1:1volume ratio and further mixing trifluoroacetic acid (TFA) at 0.1%volume ratio in the solution. The mobile phase is flowed at 1.2 mL/minthrough a size-exclusion HPLC column maintained at ambient temperature(233080-7830, 300 mm×7.8 mm, Sepax Technologies). 25 uL of eachcoformulation sample is injected and monitored at 276 nm using aUV-Visible detector for 15 minutes. Main peak and high molecular weightpolymer (HMWP) are reported as an area percent from main peak region atapproximately 5.6 mins retention time and HMWP region between 4 and 5.2mins. The data is collected at different points during the 36-dayincubation period at 30° C. Using slope analysis, the rate of change ofHMWP per day is performed using Y by X plots using commercial software.

TABLE 3 Tabulated rates of change (%/day) for main peak loss and HMWPgrowth over time as determined by analytical RP-HPLC. Change in HMWPSample (%/Day) Humalog U200 + 0.01 mg/mL meloxicam 0.0091 Humalog U200 +0.05 mg/mL meloxicam 0.0091 Humalog U200 + 0.18 mg/mL meloxicam 0.0082Humalog U200 + 0.27 mg/mL meloxicam 0.0079 Humalog U200 control 0.0079Humalog U200 + 0.075 mg/mL bromfenac sodium 0.0079 Humalog U200 + 0.187mg/mL bromfenac sodium 0.0089 Humalog U200 + 0.746 mg/mL bromfenacsodium 0.00122

<1.5 mg/ml is not a product, but 0.746 is highest concentration effecton polymer formation, as bromfenac increases, meloxicam effect is lessapparent so meloxicam and bro

Data Analysis Methodology

There are four parameters that we most often use to evaluate the effectsof an intervention on glucose pharmacodynamics: the baseline subtractedarea under the glucose PD curve (AUC); C_(min), or the maximum changefrom baseline that the insulin dose effects; T_(min), or the time ittakes to reach C_(min) after the insulin dose is administered; and the“Early 50% Tmin”, or the time it takes to first reach a glucoseconcentration that is 50% the magnitude of C_(min). Table 4 belowrepresents typical PD data for a non-diabetic swine that has been fastedand dosed with 0.15 U/kg of U100 insulin lispro, delivered via aninfusion set that has been in place for up to 10 days. Between insulindoses, the infusion set is connected to an insulin pump programmed todeliver insulin placebo at a 10 uL/h basal rate and 100 ul bolusesdelivered three times daily. SEM=standard error of the mean.

TABLE 4 Typical PD data for a non-diabetic swine Days of Std CSI N MeanSEM Dev C_(min) 0 34 −61.32 1.74 10.15 (Δ mg/dL) 3 33 −57.31 1.88 10.795 30 −58.16 2.37 13 7 29 −45.12 3.64 19.63 10 26 −30.44 3.18 16.23T_(min) 0 34 69.26 7.33 42.75 (min) 3 33 52.73 6.69 38.45 5 30 40 3.921.33 7 29 69.3 17 91.5 10 26 96.9 20 101.9 AUC 0 34 −13196 602 3511(min*mg/dL) 3 33 −9702 529 3039 5 30 −8277 620 3394 7 29 −6115 566 304910 26 −4213 509 2595

As is demonstrated above by the shift in PD parameters from day 0 to day3, starting at around day 2 of continuous subcutaneous insulin infusion(CSII), insulin uptake becomes faster, and depending on pump speed, someloss in AUC may also be observed. This phenomenon has been wellcharacterized by researchers (sometimes referred to as the “Tamborlaneeffect”) and is well-tolerated by patients. Thus, a solution to enablingextended infusion site efficacy should strive to achieve some level ofequivalence to the glycemic control patients experience on day 3 ofCSII. In the interventions set forth herein, we have thus evaluated theresulting PD performance against the standard of care (a rapid-actinginsulin such as Humalog®) after 3 days of CSII. Data from swine studiesset forth in Tables 5, 6, and 7 show the efficacy of three formulationsat days 0, 3, 5, 7, and 10 normalized against U100 Humalog values on day3.

TABLE 5 Glucose Area Under the Curve v. Standard of Care Day 3 GlucoseAUC % Difference vs U100 Humalog AUC on Day 3 (mean of −10608 min*mg/dL,n = 53) Formulation Metric Day 0 Day 3 Day 5 Day 7 Day 10 U100 Humalog +n 19 19 19 19 18 0.025 mg/mL Mean (min*mg/dL) −12798 −11005 −10145 −6650−5287 Meloxicam % Difference 21%  4% −4% −37% −50% p-value 0.036 0.7040.658 0.000 0.000 n 14 14 14 14 13 U100 Humalog + Mean (min*mg/dL)−14675 −8205 −7496 −8219 −5950 0.050 mg/mL % Difference 38% −23%  −29% −23% −44% Meloxicam p-value 0.001 0.049 0.011 0.050 0.000 U100 Humalog +n 18 19 19 19 19 0.70 mg/mL Mean (min*mg/dL) −16184 −12471 −11005 −8360−7504 Bromfenac % Difference 53% 18%  4% −21% −29% Sodium p-value 0.0000.099 0.725 0.047 0.006

TABLE 6 Glucose Cmin % v. Standard of Care Day 3 Glucose Cmin %Difference vs U100 Humalog Cmin on Day 3 (mean of −59 mg/dL, n = 53)Formulation Metric Day 0 Day 3 Day 5 Day 7 Day 10 U100 Humalog + N 19 1919 19 18 0.025 mg/mL Mean (Δ mg/dL) −56 −60 −60 −54 −33 Meloxicam %Difference −5%  1%  2% −8% −44% p-value 0.468 0.856 0.817 0.248 0.000U100 Humalog + n 14 14 14 14 13 0.050 mg/mL Mean (Δ mg/dL) −61 −55 −57−57 −45 Meloxicam % Difference 2% −8%  −4% −4% −24% p-value 0.773 0.3460.667 0.656 0.005 U100 Humalog + n 18 19 19 19 19 0.70 mg/mL Mean (Δmg/dL) −62 −60 −58 −52 −46 Bromfenac % Difference 5% 1% −3% −13%  −22%Sodium p-value 0.524 0.935 0.735 0.085 0.004

TABLE 7 Glucose Tmin % v. Standard of Care Day 3 Glucose Tmin %Difference vs U100 Humalog Tmin on Day 3 mean of 41 min, n = 53)Formulation Metric Day 0 Day 3 Day 5 Day 7 Day 10 U100 Humalog + n 19 1919 19 18 0.025 mg/mL Mean (min) 56 29 33 68 144 Meloxicam % Difference37% −29% −19%  68% 253%  p-value 0.338 0.452 0.616 0.078 0.000 U100Humalog + n 14 14 14 14 13 0.050 mg/mL Mean (min) 72 53 55 50 52Meloxicam % Difference 76%  29% 34% 24% 27% p-value 0.084 0.513 0.4390.592 0.555 U100 Humalog + n 18 19 19 19 19 0.70 mg/mL Mean (min) 64 4359 47 60 Bromfenac Sodium % Difference 56%  6% 45% 16% 47% p-value 0.1770.879 0.270 0.696 0.250

1. A pharmaceutical composition comprising insulin, a preservative, andat least one agent selected from the group consisting of meloxicam,bromfenac sodium, acetylsalicylic acid, salicylic acid, dexamethasone,heparin, and paracetamol.
 2. A pharmaceutical composition as claimed byclaim 1, comprising insulin, a preservative, and at least one agentselected from the group consisting of acetylsalicylic acid, salicylicacid, dexamethasone, heparin, and paracetamol.
 3. A pharmaceuticalcomposition as claimed by claim 1 wherein the insulin is arapid-acting-insulin.
 4. A pharmaceutical composition as claimed byclaim 1 wherein the insulin is ultra-rapid-acting insulin.
 5. Apharmaceutical composition as claimed by claim 1 wherein the insulin isinsulin lispro.
 6. A pharmaceutical composition as claimed by claim 1wherein the insulin is human insulin.
 7. A pharmaceutical composition asclaimed by claim 1 wherein the insulin concentration is from about 40U/mL to about 1000 U/mL.
 8. A pharmaceutical composition as claimed byclaim 7 wherein the insulin concentration is from about 40 U/mL to about500 U/mL.
 9. A pharmaceutical composition as claimed by claim 8 whereinthe insulin concentration is from about 100 U/mL to about 500 U/mL. 10.A pharmaceutical composition as claimed by claim 9 wherein the insulinconcentration is from about 100 U/mL to about 200 U/mL.
 11. Apharmaceutical composition as claimed by claim 10 wherein the insulinconcentration is about 100 U/mL.
 12. A pharmaceutical composition asclaimed by claim 7 wherein the preservative is at least one selectedfrom the group consisting of phenol and m-cresol.
 13. A pharmaceuticalcomposition as claimed by claim 12 wherein the preservativeconcentration is in a range of about 2.5 mg/mL to about 3.8 mg/mL.
 14. Apharmaceutical composition as claimed by claim 13 wherein thepreservative is m-cresol in a concentration range of about 3.0 mg/mL toabout 3.5 mg/mL.
 15. A pharmaceutical composition as claimed by claim 14wherein the preservative is m-cresol in a concentration of about 3.15mg/mL.
 16. A pharmaceutical composition as claimed by claim 12 whereinthe preservative is phenol in a concentration range of about 2.5 mg/mLto about 3.8 mg/mL.
 17. A pharmaceutical composition as claimed by claim12 wherein the preservative is a mixture of m-cresol at a concentrationrange of from about 0.1 mg/mL to about 3.8 mg/mL and phenol at aconcentration range of from about 0.1 mg/mL to about 3.8.
 18. Apharmaceutical composition as claimed by claim 17 wherein thepreservative is a mixture of m-cresol at a concentration of from about1.6 to about 1.75 mg/mL and phenol at a concentration of from about 1.4to about 1.6 mg/mL.
 19. A pharmaceutical composition as claimed by claim1 wherein the agent is selected from the group consisting of salicylicacid, acetylsalicylic acid, and paracetamol.
 20. A pharmaceuticalcomposition as claimed by claim 19 wherein the agent is salicylic acid.21. A pharmaceutical composition as claimed by claim 20 wherein thesalicylic acid concentration is from about 1.8 mg/mL to about 1600mg/mL.
 22. A pharmaceutical composition as claimed by claim 20 whereinthe salicylic acid is a concentration is from about 10 mM to about 20mM.
 23. A pharmaceutical composition as claimed by claim 22 wherein thesalicylic acid is a concentration of about 10 mM.
 24. A pharmaceuticalcomposition as claimed by claim 19 wherein the agent is paracetamol. 25.A pharmaceutical composition as claimed by claim 24 wherein theparacetamol concentration is from about 0.4 mg/mL to about 900 mg/mL 26.A pharmaceutical composition as claimed by claim 25 wherein theparacetamol concentration is about 30 mM.
 27. A pharmaceuticalcomposition as claimed by claim 19 wherein the agent is acetylsalicylicacid.
 28. A pharmaceutical composition as claimed by claim 27 whereinthe acetylsalicylic acid concentration is from about 1.8 mg/mL to about1600 mg/mL.
 29. A pharmaceutical composition as claimed by claim 27wherein the acetylsalicylic acid is a concentration is from about 10 mMto about 20 mM.
 30. A pharmaceutical composition as claimed by claim 29wherein the acetylsalicylic acid is a concentration of about 10 mM. 31.A pharmaceutical composition as claimed by claim 18 wherein the agent isdexamethasone.
 32. A pharmaceutical composition as claimed by claim 31wherein the dexamethasone is a concentration of 0.004 mg/mL to about5.75 mg/mL.
 33. A pharmaceutical composition as claimed by claim 32wherein the dexamethasone is a concentration of about 1 mg/mL to about 5mg/mL.
 34. A pharmaceutical composition as claimed by claim 18 whereinthe agent is heparin.
 35. A pharmaceutical composition as claimed byclaim 34 wherein the heparin is a concentration of about 1.2 U/mL toabout 1200 U/mL.
 36. A pharmaceutical composition as claimed by claim 35wherein the heparin is a concentration of about 1.2 U/mL to about 267U/mL.
 37. A pharmaceutical composition as claimed by claim 1 wherein theagent is meloxicam.
 38. A pharmaceutical composition as claimed by claim37 wherein the meloxicam is a concentration of about 0.015 mg/mL toabout 5.0 mg/mL.
 39. A pharmaceutical composition as claimed by claim 38the meloxicam is a concentration of about 1.5 mg/mL to about 3.0 mg/mL.40. A pharmaceutical composition as claimed by claim 18 wherein theagent is bromfenac sodium.
 41. A pharmaceutical composition as claimedby claim 40 wherein the bromfenac sodium is a concentration of about 0.1mg/mL to about 7.0 mg/mL.
 42. A pharmaceutical composition as claimed byclaim 41 wherein the bromfenac sodium is a concentration of about 0.5mg/mL to about 3.0 mg/mL.
 43. A pharmaceutical composition as claimed byclaim 18 further comprising a surfactant.
 44. A pharmaceuticalcomposition as claimed by claim 43 further comprising a. Zinc, in aconcentration range of 2-4 mols zinc ions/hexamer.
 45. A pharmaceuticalcomposition as claimed by claim 44 wherein the pH of the composition isin a range of pH 7.0 to 7.8.
 46. A pharmaceutical compositioncomprising: a. insulin; b. zinc, in a concentration from about 0.2 mM toabout 1 mM; c. a preservative; d. at least one agent selected from thegroup consisting of meloxicam, bromfenac sodium, acetylsalicylic acid,salicylic acid, and paracetamol.
 47. A pharmaceutical composition asclaimed by claim 46 comprising: a. insulin; b. zinc, in a concentrationfrom about 0.2 mM to about 1 mM; c. a preservative; d. at least oneagent selected from the group consisting of acetylsalicylic acid,salicylic acid, and paracetamol.
 48. A pharmaceutical composition asclaimed by any one of claim 46 wherein the composition further comprisesa surfactant.
 49. A pharmaceutical composition as claimed by claim 48wherein the surfactant is poloxamer
 188. 50. A pharmaceuticalcomposition as claimed by claim 48 wherein the surfactant is polysorbate20.
 51. A pharmaceutical composition as claimed by claim 50, wherein theinsulin concentration is from about 100 U/mL to about 500 U/mL.
 52. Apharmaceutical composition as claimed by claim 51, wherein the insulinconcentration i about 100 U/mL or about 200 U/mL.
 53. A pharmaceuticalcomposition as claimed by claim 46 wherein the insulin is rapid-actinginsulin.
 54. A pharmaceutical composition as claimed by claim 46 whereinthe insulin is insulin lispro.
 55. A pharmaceutical composition asclaimed by claim 46 wherein the insulin is an ultra-rapid-actinginsulin.
 56. The pharmaceutical composition as claimed claim 46, whereinthe preservative is m-cresol.
 57. The pharmaceutical composition ofclaim 56, wherein the concentration of m-cresol is from about 2.5 toabout 3.8 mg/mL.
 58. The pharmaceutical composition of claim 57, whereinthe concentration of m-cresol is about 3.15 mg/mL.
 59. A pharmaceuticalcomposition as claimed by claim 46 wherein the agent is salicylic acid.60. A pharmaceutical composition as claimed by claim 46 wherein theagent is acetylsalicylic acid.
 61. A pharmaceutical composition asclaimed by claim 46 wherein the agent is paracetamol.
 62. Apharmaceutical composition as claimed by claim 48 wherein the agent ismeloxicam.
 63. A pharmaceutical composition as claimed by claim 48wherein the agent is bromfenac sodium.
 64. A pharmaceutical compositioncomprising: a. insulin lispro, in a concentration from about 100 toabout 200 U/mL; b. zinc, in a concentration from about 0.2 mM to about 1mM; c. m-cresol, in a concentration from about 2.5 to about 3.8 mg/mL;d. at least one agent selected from the group consisting of meloxicam,bromfenac sodium, acetylsalicylic acid, salicylic acid, and paracetamol;and; e. having a pH of about 7.0 to about 7.8 at room temperature.
 65. Apharmaceutical composition as claimed by claim 64 comprising: a. insulinlispro, in a concentration from about 100 to about 200 U/mL; b. zinc, ina concentration from about 0.2 mM to about 1 mM; c. m-cresol, in aconcentration from about 2.5 to about 3.8 mg/mL; d. at least one agentselected from the group consisting of acetylsalicylic acid, salicylicacid, and paracetamol and; having a pH of about 7.0 to about 7.8 at roomtemperature.
 66. A pharmaceutical composition comprising: a. insulinlispro, in a concentration of about 200 IU/mL; b. zinc, in aconcentration of about 0.8 mM; c. m-cresol, in a concentration of about3.15 mg/mL; and d. at least one agent selected from the group consistingof salicylic acid and acetaminophen.
 67. A pharmaceutical composition asclaimed by claim 66 wherein the agent is salicylic acid.
 68. Apharmaceutical composition as claimed by claim 64, wherein thecomposition is stable to allow for storage of at least 24 months at 2-8°C. and up to 28 days in-use at temperatures of up to 30° C.
 69. A methodof treating diabetes comprising administering to a human in need thereofan effective dose of the pharmaceutical composition claim
 62. 70. Thepharmaceutical composition as claimed by claim 62 for use in therapy.71. The pharmaceutical composition as claimed by claim 62 for use in thetreatment of diabetes.
 72. Use of the pharmaceutical composition asclaimed by claim 62 in the manufacture of a medicament for the treatmentof diabetes.
 73. An article of manufacture comprising any one of thepharmaceutical compositions as claimed by claim
 1. 74. An article ofmanufacture as claimed by claim 73 wherein the article of manufacture isa multi-use vial.
 75. An article of manufacture as claimed by claim 73the article of manufacture is a multi-use cartridge.
 76. An article ofmanufacture as claimed by claim 73 the article of manufacture is a pumpdevice for continuous subcutaneous insulin infusion therapy.